Stimulant dependence is an important problem in the U.S. Relapse is a frequent and complex phenomenon that occurs within one year in more than 50% of people with stimulant dependence that seeks treatment. Although the cognitive and neural mechanisms that underlie relapse are not well understood, it appears that they are closely related to basic decision-making processes. This proposal builds on work that has been accomplished in a previous R21 aimed to determine the neural substrates that underlie decision-making dysfunctions in treatment seeking methamphetamine dependent subjects. We have assembled a model to clarify the role of neural substrates in cognitive candidate mechanisms underlying decision-making as well as their dysfunction in substance dependent subjects. This proposal focuses on examining three candidate mechanism dysfunctions proposed in this model. Specifically, we will use three decision-making tasks during functional magnetic resonance imaging to probe trend detection, error processing, and risk-taking. We will focus on three 'cortical epicenters' underlying these candidate mechanisms: (1) inferior prefrontal cortex (ventromedial and ventrolateral prefrontal cortex), (2) anterior cingulate and inferior parietal Iobule, and (3) anterior insula and posterior parietal cortex. Our preliminary data indicate that neural activation patterns during decision-making tests may be a sensitive indicator for relapse susceptibility. Our specific aims are, first, to extend our finding from methamphetamine to other psychostimulants. We will compare decision-making characteristics and neural substrate activation patterns in methamphetamine dependent and cocaine dependent with those of normal comparison subjects. Second, we will prospectively follow methamphetamine dependent subjects using a comprehensive assessment of relapse factors to determine which altered candidate mechanism(s) and which neural substrate activation patterns best predict relapse susceptibility in these individuals. Accomplishing these aims would provide evidence that (1) specific cognitive mechanisms underlying decision-making are dysfunctional in subjects with stimulant use disorders; (2) these dysfunctions can be linked to specific neural substrates; (3) one can utilize computerized behavioral tests to obtain an estimate of relapse susceptibility. This project will link systems neuroscience with clinical research in substance use disorders thereby providing cognitive neuroscience and neuroimaging insights into dysfunctions associated with substance use disorders.